Project Summary/Abstract Radiation therapy is one of the primary therapeutic techniques for treating cancer. Nearly two-thirds of all cancer patients will receive radiation therapy during their illness, with an average of 29 radiation treatment episodes. Although largely effective, radiation therapy, like other forms of cancer treatment, has difficulty killing hypoxic regions within solid tumors. Cellular hypoxia is associated with radiotherapy resistance, resulting in the incomplete killing of cancer cells, and leading to recurrence and relapse. Thus, developing techniques to target the hypoxic core of tumors is a major goal of cancer research. Nearly 40% of all breast cancers and 50% of locally advanced breast cancers are hypoxic, and their altered metabolism is strongly linked to resistance to radiotherapy and systemic therapy. In prostate cancer, hypoxia is associated with early biochemical relapse after radiotherapy and also with local recurrence in the prostate gland. A variety of approaches are being used to enhance the efficacy of radiation therapy and reduce dose. These include the use of nanoparticles to enhance the radiosensitization of tumor tissue, reversing radiation resistance in tumor tissue, and increasing the radioresistance of healthy tissue. In this proposed effort, we will develop a new technique that enhances radiation treatment by using a sensitizer that both increases the energy deposited locally within the tumor and generates UV photons in the vicinity of the DNA in cancer cells. Our sensitizer consists of scintillating nanoparticles that emit UV radiation, capable of both directly damaging the DNA in hypoxic cancer cells. In addition, these particles will be composed of high atomic number elements with much higher radiation stopping power than the low atomic number elements that make up tissue. This will enhance the efficacy of the high-energy X-rays used in radiation treatment by down converting the X-ray photon energy into lower energy X-rays and particles, which have a much higher energy deposition rate (linear energy transfer, LET). We have performed a preliminary experiment, which gave encouraging results showing an increase in cell death using the LuPO4 scintillating nanoparticles. In Phase I of this effort, we will model photon transport and energy conversion, for both X-rays and UV photons, and experimentally demonstrate the effectiveness of the concept in vitro. In Phase II, we will develop size homogenous nanoparticles suitable for use in exhaustive in vitro cell experiments and preclinical studies.